This invention relates to novel compounds, to processes for preparing them, and to their use as therapeutic agents.
U.S. Pat. No. 4,022,900 (Marion) discloses benzamido-tetrahydroisoquinolines having anti-hypertensive and vasodilator properties.
PCT/GB98/00781 (SmithKline Beecham), unpublished at the filing date of this application, discloses that benzamide compounds of formula (A) below possess anti-convulsant activity and are therefore believed to be useful in the treatment and/or prevention of anxiety, mania, and related depression disorders. 
where;
R1 is hydrogen, C1-6 alkyl (optionally substituted by hydroxy or C1-4alkoxy), C1-6alkenyl, C1-6alkynyl, C1-6alkylCOxe2x80x94, formyl, CF3COxe2x80x94 or C1-6alkylSO2xe2x80x94,
R2 is hydrogen or up to three substituents selected from halogen, NO2, CN, N3, CF3Oxe2x80x94, CF3Sxe2x80x94, CF3COxe2x80x94, trifluoromethyldiazirinyl, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, C1-6perfluoroalkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-4alkyl-, C1-6alkylOxe2x80x94, C1-6alkylCOxe2x80x94, C3-6cycloalkylOxe2x80x94, C3-6cycloalkylCOxe2x80x94, C3-6cycloalkyl-C1-4alkylOxe2x80x94, C3-6cycloalkyl-C1-4alkylCOxe2x80x94, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C1-4alkyl-, C1-6alkylSxe2x80x94, C1-6alkylSO2xe2x80x94, (C1-4alkyl)2NSO2xe2x80x94, (C1-4alkyl)NHSO2xe2x80x94, (C1-4alkyl)2NCOxe2x80x94, (C1-4alkyl)NHCOxe2x80x94 or CONH2;
or xe2x80x94NR5R6 where R5 is hydrogen or C1-4 alkyl, and
R6 is hydrogen, C1-4alkyl, formyl, xe2x80x94CO2C1-4alkyl or xe2x80x94COC1-4alkyl;
or two R2 groups together form a carbocyclic ring that is saturated or unsaturated and unsubstituted or substituted by xe2x80x94OH or xe2x95x90O; and
the two R3 groups and the two R4 groups are each independently hydrogen or C1-6 alkyl or the two R3 groups and/or the two R4 groups together form a C3-6 spiroalkyl group provided that at least one R3 and R4 group is not hydrogen.
It has now been surprisingly found that carboxamide compounds of formula (I) below possess anti-convulsant activity and are therefore believed to be useful in the treatment and/or prevention of anxiety, mania, depression , panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson""s disease, psychosis, migraine, cerebral ischaemia, Alzheimer""s disease and other degenerative diseases such as Huntingdon""s chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (e.g. Giles de la Tourette""s syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS).
Accordingly, the present invention provides a compound of formula (I) or salts thereof or solvates thereof: 
wherein:
R1 is hydrogen, C1-6 alkyl (optionally substituted by hydroxy or C1-4alkoxy), C1-6alkenyl, C1-6alkynyl, C1-6alkylCOxe2x80x94, formyl, CF3COxe2x80x94 or C1-6alkylSO2xe2x80x94;
R2 is hydrogen or up to three substituents selected from halogen, NO2, CN, N3, CF3Oxe2x80x94, CF3Sxe2x80x94, CF3COxe2x80x94, CF3SO2, trifluoromethyldiazirinyl, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, C1-6perfluoroalkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-4alkyl-, C1-6alkylOxe2x80x94, C1-6alkylCOxe2x80x94, C3-6cycloalkylOxe2x80x94, C3-6cycloalkylCOxe2x80x94, C3-6cycloalkyl-C1-4alkylOxe2x80x94, C3-6cycloalkyl-C1-4alkylCOxe2x80x94, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C1-4alkyl-, C1-6alkylSxe2x80x94, C1-6alkylSO2xe2x80x94, (C1-4alkyl)2NSO2xe2x80x94,(C1-4alkyl)NHSO2xe2x80x94, (C1-4alkyl)2NCOxe2x80x94, (C1-4alkyl)NHCOxe2x80x94 and CONH2; or xe2x80x94NR5R6 where R5 is hydrogen or C1-4 alkyl, and R6 is hydrogen, C1-4alkyl, formyl, xe2x80x94CO2C1-4alkyl or xe2x80x94COC1-4alkyl; or two R2 groups together form a carbocyclic ring that is saturated or unsaturated and unsubstituted or substituted by xe2x80x94OH or xe2x95x90O;
the two R groups, the two R3 groups and the two R4 groups are each independently hydrogen, C1-6 alkyl, C1-6 alkenyl, benzyl, or phenyl, or the two R groups and/or the two R3 groups and/or the two R4 groups together form a C3-6 spiroalkyl group, provided that at least one R , R3 or R4 group is other than hydrogen; and
X is selected from the group consisting of hydrogen, halogen, cyano, CF3, alkyl and alkoxy;
provided that when X is hydrogen. the two R groups are not both hydrogen.
The compounds of this invention are typically isoquinolinyl-carboxamides, especially (tetrahydroisoquinolin-5-yl) and (tetrahydroisoquinolin-7-yl)carboxamides. The carboxamide moiety may be a benzamide. When two R2 groups form a carbocyclic ring, this is typically a 5-7 membered ring, and the carboxamide moiety may be a naphthalene carboxamide or an indane or indanone carboxamide.
In the formula (I), alkyl groups, including alkyl groups that are part of other moieties, such as alkoxy or acyl, may be straight chain or branched. Phenyl groups, including phenyl groups that are part of other moieties, in R2 may optionally be substituted with one or more independently selected halogen or C1-6 alkyl, C1-6 alkoxy or C1-6 alkylcarbonyl.
Suitable C3-6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Suitable halo substituents include fluoro, chloro, iodo and bromo.
It should be appreciated that compounds of the present invention possess chiral centres and as such may exist in different enantiomeric forms, the present invention extends to each enantiomeric form and mixtures thereof including diastereoisomers and racemates.
A preferred group of compounds of formula (I) have;
R as methyl or hydrogen; and/or
R1 as hydrogen or methyl; and/or
R2 as methyl, ethyl, iso-propyl, methoxy, ethoxy, iso-propoxy, bromo, chloro, fluoro, iodo, cyano, acetyl, CF3, or C2F5; and/or
R3 as hydrogen, methyl, or spirocyclobutyl; and/or
R4 as hydrogen, methyl, benzyl, allyl, phenyl, iso-butyl, or iso-propyl; and/or
X as hydrogen, chloro, bromo, methyl, or ethyl.
A further aspect of the invention provides a compound selected from the group consisting of;
N-(3,3-Dimethyl-1,2,3,4-tetrahydro-2-trifluoroacetyl-isoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide;
N-(3,3-Dimethyl-1,2,3,4-tetrahydro-2-trifluoroacetyl-isoquinolin-7-yl)-3-cyano-4-iso-propylbenzamide;
N-(3,3-Dimethyl-1,2,3,4-tetrahydro-2-trifluoroacetylisoquinolin-7-yl)-3-chloro-4-iso-propyloxybenzamide;
N-(3,3-Dimethyl-1,2,3,4-tetrahydro-2-trifluoroacetylisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide;
N-(3,3-Dimethyl-1,2,3,4-tetrahydro-2-trifluoroacetylisoquinolin-7-yl)-3-bromo-4-iso-propyloxybenzamide;
N-(3,3-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide;
N-(3,3-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-iso-propylbenzamide;
N-(3,3-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-iso-propyloxy-benzamide;
N-(3,3-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide;
N-(3,3-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-iso-propyloxybenzamide;
N-(2,4,4-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-iso-propyloxybenzamide;
N-(2,4,4-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-iso-propyloxybenzamide;
N-(2,4,4-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-bromo-4-ethoxy-2-methoxybenzamide;
N-(2,4,4-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl-4-iso-propyloxybenzamide;
N-(2,4,4-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-methoxybenzamide;
N-(2,4,4-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro4-methoxybenzamide;
N-(2,4,4-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-iodo-4-methoxybenzamide;
N-(2,4,4-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-fluoro-4-methoxybenzamide;
N-(2,4,4-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-methoxybenzamide:
N-(2,4,4-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-pentafluoroethylbenzamide;
N-(2,4,4-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-ethoxybenzamide;
N-(2,4,4-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-ethoxybenzamide;
N-(2,4,4-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-y )-2,4-dimethoxy-5-trifluoromethylbenzamide;
N-(2,4,4-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-methylbenzamide;
N-(2,4,4-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-ethylbenzamide;
N-(2,4,4-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3,5-dichloro-4-ethoxybenzamide;
N-(2,4,4-Trimethyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-bromo-4-ethoxy-2-methoxybenzamide;
N-(2,4,4-Trimethyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-cyano-2-ethoxy-4-iso-propylbenzamide;
N-(2,4,4-Trimethyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2-methoxy-4-iso-propyloxybenzamide;
N-(2,4,4-Trimethyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-bromo-2-methoxy-4-iso-propylbenzamide;
N-(2,4,4-Trimethyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-ethoxy-2-methoxy-5-trifluoromethylbenzamide;
N-(2,4,4-Trimethyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-cyano-2,4-diethoxy-benzamide;
N-(2,4,4-Trimethyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2,4-diethoxy-5-trifluoromethylbenzamide;
N-(2,4,4-Trimethyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxy-4-iso-propyl-5-trifluoromethylbenzamide;
N-(4,4-Dimethyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2-methoxy-4-iso-propoxybenzamide;
N-(4,4-Spirocyclopentyl-2-methyl-1,2,3,4-tetrahydroisoquin-7-yl)-3-bromo-4-ethoxybenzamide;
N-(4,4-Spirocyclopentyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethyl benzamide;
N-(4,4-Spirocyclopentyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-iso-propyl benzamide;
N-(4,4-Spirocyclopentyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-iso-propyloxybenzamide:
N-(4,4-Spirocyclopentyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethylbenzamide;
N-(2,4,4-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-ethoxy-3-trifluoromethyl-benzamide;
N-(2,4,4-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-iso-propyl-3-trifluoromethylsulfonylbenzamide;
N-(4,4-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide;
N-(8-Ethyl-2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide;
N-(8-Ethyl-2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl )-4-methoxy-3-trifluoromethylbenzamide;
N-(8-Ethyl-2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl )-3-bromo-4-iso-propyloxybenzamide;
N-(8-Ethyl-2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-iso-propylbenzamide;
N-(8-Ethyl-2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl-4-iso-propyloxybenzamide;
N-(5-Chloro-1,1,2-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-3-bromo-4-ethyl benzamide;
N-(5-Chloro-1,1,2-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-iso-propylbenzamide;
N-(5-Chloro-1,1,2-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide;
N-(5-Chloro-1,1,2-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide;
N-(1,2-Dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-4-methoxy-3-trifluoromethylbenzamide;
N-(1-Phenyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide;
N-(1-Benzyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide;
N-(1-Iso-propenyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide;
N-(1-Allyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide;
N-(1-Iso-butyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide;
N-(1-Iso-propenyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-iso-propylbenzamide;
N-(1-Iso-propenyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-iso-propoxybenzamide;
N-(1-Iso-propenyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide;
N-(1-Iso-propenyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethyl benzamide;
N-(1-Iso-propenyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-iso-propoxybenzamide;
N-(1-Iso-propyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide;
N-(1,1,2-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-iso-propyl-benzamide;
N-(1,1,2-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethylbenzamide;
N-(1,1,2-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide;
N-(1,1,2-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-iso-propoxybenzamide;
N-(2,3,3-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide;
N-(2,3,3-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-iso-propylbenzamide;
N-(2,3,3-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethylbenzamide;
N-(2,3,3-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide;
N-(2,3,3-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-iso-propoxybenzamide;
N-(4,4-Spirocyclobutyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-iso-propylbenzamide;
N-(4,4-Spirocyclobutyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide;
N-(4,4-Spirocyclobutyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-iso-propoxybenzamide;
N-(4,4-Spirocyclobutyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide;
N-(4,4-Spirocyclobutyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-ethoxy-3-trifluoromethylbenzamide;
N-(1,2,4,4-Tetramethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide;
N-(1,2,4,4-Tetramethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-iso-propoxybenzamide;
N-(1,2,4,4-Tetramethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-iso-propylbenzamide;
N-(1,2,4,4-Tetramethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-iso-propoxybenzamide;
N-(1,2,4,4-Tetramethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethylbenzamide;
N-(1,2,4,4-Tetramethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide;
N-(1,1,2,5-Tetramethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethylbenzamide;
N-(1,1,2,5-Tetramethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-iso-propylbenzamide;
N-(1,1,2,5-Tetramethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide;
N-(1,1,2-Trimethyl-5-trifluoromethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide;
N-(1,1,2-Trimethyl-5-trifluoromethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide;
N-(1,1,2-Trimethyl-5-trifluoromethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-ethoxybenzamide;
N-(2,4,4-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-ethyl-3-trifluoromethyl-benzamide;
N-(2,4,4-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl4-iso-propyl-benzamide;
N-(2,4,4-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl-4-ethoxybenzamide;
N-[4,4-Dimethyl-2-(2-methoxyethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-3-cyano-4-iso-propoxybenzamide;
N-[4,4-Dimethyl-2-(2-methoxyethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-3-cyano-4-iso-propylbenzamide;
N-[4,4-Dimethyl-2-(2-methoxyethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-4-methoxy-3-trifluoromethylbenzamide;
N-(8-Chloro-2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-iso-propoxybenzamide;
N-(8-Chloro-2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-ethyl-3-trifluoromethylbenzamide;
N-(8-Chloro-2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl-4-iso-propylbenzamide;
N-(8-Chloro-2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-methoxybenzamide;
N-(8-Chloro-2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide;
N-(8-Chloro-2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-ethoxybenzamide;
N-(8-Chloro-2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide;
N-(8-Chloro-2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-iso-propylbenzamide;
N-(8-Chloro-2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-ethylbenzamide;
N-(2,4,4-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-iso-propoxy-3-trifluoromethylbenzamide;
N-(8-Ethyl-2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-methoxybenzamide;
N-(8-Ethyl-2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro4-methoxybenzamide;
N-(8-Ethyl-2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-ethoxybenzamide;
N-(8-Ethyl-2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethylbenzamide;
N-(8-Methyl-2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide;
N-(8-Methyl-2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide;
N-(8-Methyl-2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-ethoxybenzamide;
N-(8-Methyl-2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-ethylbenzamide;
N-(8-Bromo-2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-methoxybenzamide;
N-(8-Bromo-2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide;
N-(2,4,4-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl-4-ethylbenzamide;
N-(2,4,4-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-ethoxy-3-propionylbenzamide;
N-(2,4,4-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-iso-propoxy-3-propionylbenzamide;
N-(2,4,4-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-iso-butyroyl-4-methoxybenzamide;
N-(2,4,4-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-ethoxy-3-iso-butyroyl benzamide;
N-(2,4,4-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl )-3-iso-butyroyl-4-iso-propoxybenzamide;
N-(2,4,4-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-iso-butyroyl-4-n-propoxybenzamide;
N-(4,4-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl )-3-acetyl-4-ethoxybenzamide;
N-(8-Bromo-4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide;
N-(4,4,8-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide;
N-(4,4,8-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide;
N-(4,4-Dimethyl-8-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide;
N-(4,4-Dimethyl-8-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide;
N-(4,4-Dimethyl-8-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-ethoxybenzamide;
N-(8-Cyano-2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide;
N-(4,4-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-methoxybenzamide;
N-(4,4,8-Trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl-4-ethoxybenzamide;
N-(4,4-Dimethyl-8-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl-4-ethoxybenzamide;
N-(4,4-Dimethyl-8-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl-4-methoxybenzamide;
N-(4,4-Dimethyl-8-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-propionyl benzamide;
N-(8-Chloro-4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide;
N-(8-Bromo-2,3,3-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethyl benzamide;
N-(8-Chloro-2,3,3-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-ethoxy benzamide;
N-(8-Chloro-2,3,3-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-methoxy benzamide;
N-(8-Chloro-2,3,3-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-fluoro-4-methoxy benzamide;
N-(8-Chloro-3,3-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethyl benzamide;
N-(5-Iodo-1,1,2-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethyl benzamide;
N-(5-Cyano-1,1,2-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethyl benzamide;
N-(8-Bromo-3,3-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl )-4-methoxy-3-trifluoromethylbenzamide;
N-(1,1,2,5-Tetramethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide;
N-[4,4-Dimethyl-2-(2-methoxyethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-3-bromo-4-iso-propoxybenzamide, and;
N-(6-Bromo-2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide.
When synthesised, these compounds are often in salt form, such as the hydrochloride or trifluoroacetate, and such salts also form part of this invention. Such salts may be used in preparing pharmaceutically acceptable salts. The compounds and their salts may be obtained as solvates, such as hydrates, and these also form part of this invention.
The above compounds and pharmaceutically acceptable salts thereof, especially the hydrochloride, and pharmaceutically acceptable solvates, especially hydrates, form a preferred aspect of the present invention.
The administration of such compounds to a mammal may be by way of oral, parenteral, sub-lingual, nasal, rectal, topical or transdermal administration.
An amount effective to treat the disorders hereinbefore described depends on the usual factors such as the nature and severity of the disorders being treated and the weight of the mammal. However, a unit dose will normally contain 1 to 1000 mg, suitably 1 to 500 mg, for example an amount in the range of from 2 to 400 mg such as 2, 5, 10, 20, 30, 40, 50, 100, 200, 300 and 400 mg of the active compound. Unit doses will normally be administered once or more than once per day, for example 1, 2, 3, 4, 5 or 6 times a day, more usually 1 to 4 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 1 to 1000 mg, for example 1 to 500 mg, that is in the range of approximately 0.01 to 15 mg/kg/day, more usually 0.1to 6 mg/kg/day, for example 1 to 6 mg/kg/day.
It is greatly preferred that the compound of the invention is administered in the form of a unit-dose composition, such as a unit dose oral, including sub-lingual, rectal, topical or parenteral (especially intravenous) composition.
Such compositions are prepared by admixture and are suitably adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories. Orally administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use.
Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents. tabletting agents, lubricants, disintegrants, colorants, flavourings, and wetting agents. The tablets may be coated according to well known methods in the art. Suitable fillers for use include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
These solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents. Oral formulations also include conventional sustained release formulations, such as tablets or granules having an enteric coating.
For parenteral administration, fluid unit dose forms are prepared containing the compound and a sterile vehicle. The compound, depending on the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum.
Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the.
As is common practice, the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.
Accordingly, the present invention further provides a pharmaceutical composition for use in the treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson""s disease, psychosis, migraine, cerebral ischaemia, Alzheimer""s disease and other degenerative diseases such as Huntingdon""s chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (e.g. Giles de la Tourette""s syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS) which comprises a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
The present invention also provides a method of treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson""s disease, psychosis, migraine, cerebral ischaemia, Alzheimer""s disease and other degenerative diseases such as Huntingdon""s chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (e.g. Giles de la Tourette""s syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS) comprising administering to the sufferer in need thereof an effective or prophylactic amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.
In a further aspect the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock. the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson""s disease, psychosis, migraine, cerebral ischaemia, Alzheimer""s disease and other degenerative diseases such as Huntingdon""s chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (e.g. Giles de la Tourette""s syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS).
In a further aspect the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate, thereof as a therapeutic agent, in particular for the treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson""s disease, psychosis, migraine, cerebral ischaemia, Alzheimer""s disease and other degenerative diseases such as Huntingdon""s chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (e.g. Giles de la Tourette""s syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS).
Another aspect of the invention is a process for the preparation of compounds of formula (I) as herein before described or salts thereof or solvates thereof which comprises reacting a compound of formula (II) 
where RA, R1A, R3A, R4A are R, R1, R3, R4 as defined for formula (I) or a group or groups convertible to R, R1, R3, R4 with a compound of formula (III) 
where Y is Cl or OH, and R2A groups are independently R2 as defined for formula (I) or a group or groups convertible to R2, and where required converting an RA, R1A, R2A, R3A, R4A group to a R, R1, R2, R3, R4 group, converting one R, R1, R2, R3, R4 group to another R, R1, R2, R3, R4 group, or converting a salt product to the free base or another pharmaceutically acceptable salt, or separating any enantiomers, or converting a free base product to a pharmaceutically acceptable salt.
Reaction of a compound of formula (III) which is a benzoyl chloride derivative (Y=Cl) will lead directly to the hydrochloride salt. Suitable solvents include ethyl acetate or dichloromethane, optionally in the presence of a base such as triethylamine. When the compound of formula (III) is a benzoic acid derivative (Y=OH), conventional conditions for condensation of aromatic acids with amines may be used, for example reacting the components in a mixture of ethyl-(dimethylaminopropyl)-carbodiimide/hydroxybenzotriazole in a suitable inert solvent such as dimethyl formamide.
Conversions of an RA, R1A, R2A, R3A, R4A group to a R, R1, R2, R3, R4 group typically arise when a protecting group is needed during the above coupling reaction or during the preparation of the reactants by the procedures described below. Interconversion of one R, R1, R2, R3, R4 group to another typically arises when one compound of the invention is used as the immediate precursor of another compound of the invention or when it is easier to introduce a more complex or reactive substituent at the end of a synthetic sequence.
Compounds of formula (II) when R4=H or alkyl may be prepared from the corresponding isoquinoline of formula (IV) 
by reaction with a compound R1AZ where Z is a leaving group such as halogen, especially iodo, or tosylate to obtain an intermediate of formula (V) 
which is reacted with an R4A containing Grignard reagent under conventional conditions to obtain a dihydroisoquinoline of formula (VI) 
which can be hydrogenated, for example using hydrogen and a palladium/activated carbon catalyst, to obtain a tetrahydroisoquinoline of formula (II). Alternatively the compound of formula (IV) may be a nitro-isoquinoline, and the nitro group is converted to an amino group in the hydrogenation step.
When the intended R1 is hydrogen, the N of the isoquinoline is preferably protected conventionally, for example by making R1A benzyl, or 4-methoxybenzyl during introduction of the R4 group via the Grignard reagent. Again protection is preferably provided prior to formation of the benzamide, for example by tert.-butoxycarbonyl and then deprotected under standard conditions, for example using trifluoroacetic acid/methylene chloride.
Amino/nitro-isoquinolines of formulae (IV) and the reagents used are commercially available, or can be prepared from commercially available materials using conventional procedures described in the literature (eg. I. W. Matheson et al, J. Med. Chem. 1973, 16, 332).
Compounds of formula (II) with di-R3 substitution and X is hydrogen may be prepared from the corresponding nitro-isoquinoline dione of formula (VII), by converting the nitro group to amino by catalytic hydrogenation as above and subsequently removing the dione groups by reduction with diborane. The nitro-dione may be obtained by treating a di-R3 isoquinoline dione [prepared using the procedure of H. Takechi et al., Synthesis. 1992, 778] with fuming nitric acid. R1A groups may be introduced as described above. 
Compounds of formula (II) where both R4 are alkyl may be prepared from the corresponding 1-alkyl-3,4-dihydroisoquinoline by nitration [using procedures by R. D. Larsen et al, J. Org. Chem., 1991 56 6034 and A. P. Venkov and S. S. Abeghe, Syn. Commun., 1996 26 127] followed by quaternisation and treatment with an R4 Grignard reagent as described above.
Compounds of formula (II) where R is alkyl may be prepared from the corresponding phenylethylamines using the modified Pictet-Spengler procedure of T. J. N. Watson J. Org. Chem., 1998, 63, 406.
When the substituent X is other than hydrogen it may be introduced during any of the procedures above, or may be present on commercially available starting materials usable in the above described procedures. Most suitably the substituent X is introduced into an amino/nitro compound of formula (II) in which X is hydrogen. For example X as halogen may be incorporated directly by halogenation or via an amino group using Sandmeyer chemistry as illustrated in the descriptions below. Interconversions of X=halogen to X=alkyl or trifluoroacetyl may be carried out using Pd(0) or Cu(I) chemistry respectively as detailed below.
Compounds of formula (III) may be prepared by further substitution of commercially available benzoic acid derivatives using conventional procedures, or by oxidation of corresponding substituted benzyl alcohols. Alternatively benzoic acids can be prepared from correpondingly substituted phenols, for example by formation of the acetate, conversion to an acetophenone and then to the desired acid.
Where the above described intermediates are novel compounds, they also form part of this invention.